Nicotinic acetylcholine receptors, the ligand gated ion channels at which nicotine acts, play an important role in nicotine abuse and understanding its neurobiology may be central to developing more rational approaches for nicotine abuse treatments. The in vitro characterization of the receptor-ligand interaction is an important step in understanding the action of a ligand in vivo (i.e., for interpretation of the results from the functional studies of receptors). Recently, three radiohalogenated analogs of 3-(2(S)-azetidinylmethoxy)pyridine (A-85380) have been used successfully for the in vivo visualization of alpha4beta2* nicotinic receptors in the human brain with PET/SPECT. Previously we reported the characterization of one of these radioligands 5-[I-125]iodo-3-(2(S)-azetidinylmethoxy) pyridine. We performed an in vitro characterization of the second of these radioligands, 6-[F-18]fluoro-3-(2(S)-azetidinylmethoxy) pyridine (6 [F-18]fluoro-A-85380. In human postmortem cortical tissue, 6-[F-18]fluoro-A-85380 reversibly binds with high affinity to a single population of sites (Kd =59 pM at 37?C, Bmax =0.7 pmol/g tissue). The binding is fully reversible and is characterized at 37 degrees C by a T? for the association of 2.2 min (at a ligand concentration of 39 pM) and by a T? for the dissociation of 3.6 min. 6-Fluoro-A-85380 exhibits clear selectivity for the alpha4beta2* subtype over the other major mammalian nicotinic receptor subtypes: alpha7, alpha3beta4, and muscle-type. These results suggest that 6 [F-18]fluoro-A-85380 is a promising radioligand for in vivo imaging of brain alpha4beta2* nicotinic receptors. Less upregulation of nicotinic acetylcholine receptors is found in studies of brain tissue from patients with schizophrenia who smoke than in brain tissue from mentally healthy smokers. As schizophrenic patients often take typical or atypical neuroleptics chronically, the impact of these drugs on the upregulation of alpha4beta2* nicotinic receptors by nicotine was tested in rats. Literature reports suggest that the typical neuroleptic, haloperidol, has no effect. We tested the effect of the atypical neuroleptics, risperidone and olanzapine on the upregulation of these receptors by nicotine in the thalamus, striatum and hippocampus of rats using in vitro assays with 5-[I-125]iodo-A-85380. Neither drug attenuated the effect of nicotine, which increased the density of the receptors in these areas by 50, 80 and 90%, respectively; however, risperidone given without nicotine produced a modest increase (25%) in the density of the nicotinic receptors in the striatum. Substantial anecdotal evidence suggests that nicotine may function as a gateway drug to illicit drug use. As such we utilized an animal behavorial model of drug rewards, conditioned place preference, (CPP) to test the hypothesis that nicotine produces behavioral cross-sensitization to different classes of abused drugs, specifically opiates, stimulants and marihuana. These experiments in rats demonstrated that nicotine pretreatment enhances the rewarding effects of amphetamine for at least 3 to 5 days following the cessation of nicotine, with this effect dissipating within 19 days. The underlying mechanism involves alpha4beta2 nAChRs as the competitive alpha4beta2 antagonist dihydro beta erythroidine effectively blocked the development of nicotine-induced cross sensitization. Interestingly, the alpha7 nicotinic antagonist methyllycaconitine also antagonized cross-sensitization at doses that do not block nicotine self-administration in rats. This study and published report have clearly demonstrated that nicotine produces cross-sensitization to the rewarding effects of both opiates and psychostimulants measured with CPP. The development of cross-sensitization to the rewarding effects of these drugs involves the interaction of nicotine with both alpha4beta2 and alpha7

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Intramural Research (Z01)
Project #
1Z01DA000403-08
Application #
6987766
Study Section
(NRB)
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2004
Total Cost
Indirect Cost
Name
National Institute on Drug Abuse
Department
Type
DUNS #
City
State
Country
United States
Zip Code
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Gundisch, Daniela; Koren, Andrei O; Horti, Andrew G et al. (2005) In vitro characterization of 6-[18F]fluoro-A-85380, a high-affinity ligand for alpha4beta2* nicotinic acetylcholine receptors. Synapse 55:89-97
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